This invention relates to a process for preparing certain 4-hydroxy indole, indazole and 4-hydroxy carbozole compounds useful as intermediates for preparing compounds useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock.
Certain 1H-indole-3-glyoxamides are known to be potent and selective inhibitors of mammalian sPLA2 useful for treating diseases, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related sPLA2 induced diseases. EPO publication No. 0675110, for example, discloses such compounds.
Various patents and publications describe processes for making these compounds using 4-hydroxy indole intermediates.
The article, xe2x80x9cRecherches en serie indolique. VI sur tryptamines substitueesxe2x80x9d, by Marc Julia, Jean Igolen and Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060-1068, describes certain indole-3-glyoxylamides and their conversion to tryptamine derivatives.
The article, xe2x80x9c2-Aryl-3-Indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)xe2x80x9d by E. Romeo, et al., The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3-indolglyoxylamides having research applications in mammalian central nervous systems.
The abstract, xe2x80x9cFragmentation of N-benzylindoles in Mass Spectrometryxe2x80x9d; Chemical Abstracts, Vol. 67, 1967, 73028h, reports various benzyl substituted phenols including those having glyoxylamide groups at the 3 position of the indole nucleus.
U.S. Pat. No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus.
U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
U.S. Pat. No. 2,825,734 describes the preparation of 3-(2-amino-1-hydroxyethyl)indoles using 3-indoleglyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30).
U.S. Pat. No. 4,397,850 prepares isoxazolyl indolamines using glyoxylamide indoles as intermediates.
U.S. Pat. No. 3,801,594 describes analgesics prepared using 3-indoleglyoxylamide intermediates.
The article, xe2x80x9cNo. 565.xe2x80x94Inhibiteurs d""enzymes. XII.xe2x80x94Preparation de (propargylamino-2 ethyl)-3 indolesxe2x80x9d by A. Alemanhy, E. Fernandez Alvarez, O. Nieto Lopey and M. E. Rubic Herraez; Bulletin De La Societe Chimique De France, 1974, No. 12, pp. 2883-2888, describes various indolyl-3 glyoxamides which are hydrogen substituted on the 6-membered ring of the indole nucleus.
The article xe2x80x9cIndol-Umlagerung von 1-Diphenylamino-2,3-dihydro-2,3-pyrrolidonenxe2x80x9d by Gert Kollenz and Christa Labes; Liebigs Ann. Chem., 1975, pp. 1979-1983, describes phenyl substituted 3-glyoxylamides.
Many of these processes employ a 4-hydroxy indole intermediate. For example U.S. Pat. No. 5,654,326 U.S., herein incorporated by reference in its entirety, discloses a process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives comprising reacting an appropriately substituted 4-methoxyindole (prepared as described by Clark, R. D. et al., Synthesis, 1991, pp 871-878, the disclosures of which are herein incorporated by reference) with sodium hydride in dimethylformamide at room temperature (20-25xc2x0 C.) then treating with arylmethyl halide at ambient temperatures to give the 1-arylmethylindole which is O-demethylated using boron tribromide in methylene chloride (Tsung-Ying Shem and Charles A. Winter, Adv. Drug Res., 1977, 12, 176, the disclosure of which is incorporated by reference) to give the 4-hydroxyindole. Alkylation of the hydroxy indole is achieved with an alpha bromoalkanoic acid ester in dimethylformamide using sodium hydride as a base. Conversion to the glyoxamide is achieved by reacting the xe2x88x9d-[(indol-4-yl)oxy]alkanoic acid ester first with oxalyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in methanol.
The process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives, as set forth above, has utility. However, this process uses expensive reagents and environmentally hazardous organic solvents, produces furan containing by-products and results in a relatively low yield of desired product.
In an alternate preparation an appropriately substituted propronylacetate is halogenated with sulfuryl chloride. The halogenated Intermediate is hydrolyzed and decarboxylated by treatment with hydrochloric acid then reacted with an appropriately substituted cyclohexane dione. Treatment of the alkylated dione with an appropriate amine affords a 4-keto-indole which is oxidized by refluxing in a high-boiling polar hydrocarbon solvent such as carbitol in the presence of a catalyst, such as palladium on carbon, to prepare the 4-hydroxyindole which may then be alkylated and converted to the desired glyoxamide as described above.
This process however is limited by the required high temperature oxidation and requires recovery of a precious metal catalyst.
While the methods described above for preparing the 4-hydroxy indole intermediate are satisfactory, a more efficient transformation is desirable.
The present invention provides an improved process for preparing 4-hydroxy-indole intermediates. The process of the present invention can be performed with inexpensive, readily available, reagents under milder conditions. In addition, the present process allows for transformation with a wider variety of substituents on the indole platform. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
The present invention provides a process for preparing a compound of the formula I 
wherein:
Y is xe2x80x94CR4 or xe2x80x94Nxe2x80x94;
R4 is H, xe2x80x94(C1-C6)alkyl or when taken together with R2 forms a cyclohexeny ring
R2 is non-interfering substituent;
R3 is a non-interfering substituent;
m is 1-3 both inclusive; and
R1 is selected from groups (a), (b) and (c) where;
(a) is xe2x80x94(C1-C20)alkyl, xe2x80x94(C2-C20)alkenyl, xe2x80x94(C2-C20)alkynyl, carbocyclic radicals, or heterocyclic radicals, or
(b) is a memeber of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L)xe2x80x94R80); where, (L)xe2x80x94 is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in xe2x80x94(L)xe2x80x94 are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only, (v) carbon, hydrogen, and one sulfur only, and (vi) an carbon, hydrogen, and oxygen only; and where R80 is a group selected from (a) or (b);
which process comprises oxidizing a compound of formula III 
by heating with a base and a compound of the formula 
where R is xe2x80x94(C1-C6)alkyl or aryl and X is xe2x80x94(C1-C6)alkoxy, halo or xe2x80x94OCO2(C1-C6)alkyl.
The invention provides in addition novel reagents of the formula 
where R is xe2x80x94(C1-C6)alkyl, aryl or substituted aryl; and
X is xe2x80x94OCO1 (C1-C6)alkyl provided that when X is xe2x80x94OCO2CH3, R cannot be tolulyl.
The present invention provides, in addition novel intermediates of the formula 
wherein:
R is xe2x80x94(C1-C6)alkyl, aryl or substituted aryl,
Y is xe2x80x94CR4 or xe2x80x94Nxe2x80x94;
R4 is H, xe2x80x94(C1-C6)alkyl or when taken together with R2 forms a cyclohexeny ring
R2 is non-interfering substituent;
R3 is a non-interfering substituent;
m is 1-3; and
R1 is selected from groups (a), (b) and (c) where;
(a) is xe2x80x94(C1-C20)alkyl, xe2x80x94(C2-C20)alkenyl, xe2x80x94(C2-C20,)alkynyl, carbocyclic radicals, or heterocyclic radicals, or
(b) is a memeber of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L)xe2x80x94R80; where, (L)xe2x80x94 is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in xe2x80x94(L)xe2x80x94 are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only, (v) carbon, hydrogen, and one sulfur only, and (vi) an carbon, hydrogen, and oxygen only; and
where R80 is a group selected from (a) or (b).
Such intermediates are useful for preparing compounds useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
The compounds of the invention employ certain defining terms as follows:
As used herein, the term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term xe2x80x9calkylxe2x80x9d includes xe2x80x94(C1-C2)alkyl, xe2x80x94(xe2x88x92C4)alkyl, xe2x80x94(C1-C6)alkyl, xe2x80x94(C5-C14)alkyl, and xe2x80x94(C1-C10)alkyl.
The term xe2x80x9calkenylxe2x80x9d as used herein represents an olefinically unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains.
The term xe2x80x9calkynylxe2x80x9d denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes. The term xe2x80x9c(C1-C10) alkoxyxe2x80x9d, as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxyl, heptoxy, hexoxy, octoxy, nonoxy, decoxy and like groups, attached to the remainder of the molecule by the oxygen atom. The term (C1-C10)alkoxy includes (C1-C6)alkoxy.
The term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
The term xe2x80x9carylxe2x80x9d means a group having the ring structure characteristic of benzene, pentalene, indene, naphthalene, azulene, heptalene, phenanthrene, anthracene,etc. The aryl group may be optionally substituted with 1 to 3 substituents selected from the group consisting of (C1-C6)alkyl (preferably methyl), (C1-C6)alkoxy or halo (preferable fluorine or chlorine).
The term, xe2x80x9cheterocyclic radicalxe2x80x9d, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
The term xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyi, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is an integer from 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to hydrogen, xe2x80x94(C1-C14)alkyl, xe2x80x94(C2-C6)alkenyl, xe2x80x94(C2-C6)alkynyl, xe2x80x94(C7-C12)aralkyl, xe2x80x94(C7-C12)alkaryl, xe2x80x94(C3-C8)cycloalkyl, xe2x80x94(C3-C8)cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C2-C6)alkenyloxy, xe2x80x94(C2-C6)alkynyloxy, xe2x80x94(C1-C12)alkoxyalkyl, xe2x80x94(C1-C12)alkoxyalkyloxy, xe2x80x94(C1-C12)alkylcarbonyl, xe2x80x94(C1-C12)alkylcarbonylamino, xe2x80x94(C1-C12)alkoxyamino, xe2x80x94(C1-C12)alkoxyaminocarbonyl, xe2x80x94(C1-C12)alkylamino, xe2x80x94(C1-C6)alkylthio, xe2x80x94(C1-C12)alkylthiocarbonyl, xe2x80x94(C1-C6)alkylsulfinyl, xe2x80x94(C1-C6)alkylsulfonyl, xe2x80x94(C1-C6)haloalkoxy, xe2x80x94(C1-C6)haloalkylsulfonyl, xe2x80x94(C1-C6)haloalkyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(CH2)nCN, xe2x80x94(CH2)nNR9R10, xe2x80x94C(O)O(C1-C6alkyl), xe2x80x94(CH2)nO(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio; xe2x80x94(CONHSO2)R15, where R15 is xe2x80x94(C1-C6)alkyl; xe2x80x94CF3, naphthyl or xe2x80x94(CH2)sphenyl where s is 0-5; xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, pyridyl, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nCO2H, cyano, cyanoguanidinyl, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiccarbonyl, furyl, thiophenyl xe2x80x94COR9, xe2x80x94CONR9R10, xe2x80x94NR9R10, xe2x80x94NCHCOR9, xe2x80x94SO2R9, xe2x80x94OR9, xe2x80x94SR9, CH2SO2R9, tetrazolyl or tetrazolyl substituted with xe2x80x94(C1-C6)alkyl, phenyl or xe2x80x94(C1-C4)alkylphenyl, xe2x80x94(CH2)nOSi(C1-C6)alkyl and (C1-C6)alkylcarbonyl; where n is from 1 to 8 and R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C2-C4)alkylphenyl or -phenyl(C1-C4)alkyl.
A preferred group of compounds of formula I prepared by the process of the instant invention are those wherein:
Y is CR4 where R4 is H or when taken together with R2 forms a cyclohexenyl ring;
R3 is H, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy (C1-C6)alkenyl; or xe2x80x94(CH2)nR8 where R8 is H, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl where R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl or -phenyl (C1-C4)alkyl and n is 1 to 8; and
R1 is H, xe2x80x94(C5-C14)alkyl, xe2x80x94(C3-C14)cycloalkyl, pyridyl, phenyl or phenyl substituted with from 1-5 substituents selected from the group consisting of xe2x80x94(C1-C6)alkyl, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94(C1-C4)alkoxy, xe2x80x94CN, xe2x80x94(C1-C4)alkylthio, phenyl(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl, phenyl, phenoxy, xe2x80x94OR9; where R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl or -phenyl(C1-C4); tetrazole; tetrazole substituted with xe2x80x94(C1-C4)alkyl or xe2x80x94(C1-C4)alkylphenyl; or naphthyl.
The process of the present invention provides an improved method for synthesizing the compounds of formula I using inexpensive, readily available reagents as shown in Scheme I as follows. 
Ketone (III) is dissolved in a suitable solvent preferably an aprotic solvent such as THF. Other suitable solvents include but are not limited to DMF, dioxane, or toluene. The substrate/solvent solution may be sonicated or heated slightly, if necessary to facilitate dissolution.
The amount of solvent used should be sufficient to ensure that all compounds stay in solution until the desired reaction is complete.
The solution is treated with a base, preferably a strong base such as sodium hydride, then with a sulfinating agent of the formula 
where R is xe2x80x94(C1-C6)alkyl, aryl or substituted aryl and X is (C1-C6)alkoxy, halo or xe2x80x94OCO2(C1-C6)alkyl. The sulfinating reagent may be prepared according to the procedure of J. W. Wilt et al., J. Org. Chem, 1967, 32, 2097. Preferred sulfinating agents include methyl p-tolyl sulfinate, methylbenzene sulfinate or p-toluylsulfinic isobutyric anhydride. Other suitable bases include but are not limited to LDA, sodium methoxide, or potassium methoxlde. Preferably two equivalents of base are used. Preferably, when sodium hydride is employed, the base is added before the sulfinating reagent. The order of addition of reagents is not important when sodium methoxide is used.
The reaction may be conducted at temperatures from about 25xc2x0 C. to reflux, preferably at reflux and is substantially complete in from one to 24 hours.
The amount of sulfinating reagent is not critical, however, the reaction is best accomplished using a molar equivalent or excess relative to the starting material (III).
The above reactions may be run as a xe2x80x9cone potxe2x80x9d process with the reactants added to the reaction vessel in the order given above, preferably with an acid quench of the base prior to reflux.
Dioxane is a preferred solvent in a xe2x80x9cone partxe2x80x9d process. THF and toluene, respectively, are preferred solvents if a xe2x80x9ctwo potxe2x80x9d process is employed.
The intermediate (II) can be isolated and purified using standard crystalization or chromatographic procedures.
Standard analytical techniques such as TLC or HPLC can be used to monitor the reactions in order to determine when the starting materials and intermediates are converted to product.
In an alternate preparation, the sulfinating reagent can be replaced with a disulfide compound of the formula R20SSR20 where R20 is alkyl or aryl. Oxidation of the sulfide intermediate can then be readily achieved using an appropriate oxidizing reagent such as hydrogen peroxide or m-chloroperbenzoic acid.
It will be readily appreciated by the skilled artisan that the starting materials for all of the above procedures are either commercially available or can be readily prepared by known techniques from commercially available starting materials. For example, when X is N, starting material (1) can be prepared according to the procedure of Peet, N. P., et al,. Heterocycles, Vol. 32, No. 1, 1991, 41.
When Y is xe2x80x94CH2R4, starting material V, is prepared according to the following procedure. 
R8 is xe2x80x94(C1-C6)alkyl or aryl
R30 is H or xe2x80x94(C1-C6)alkyl
An appropriately substituted propionyl acetate X is first halogenated by treatment with sulfuryl chloride, preferably a. equimolar concentrations relative to the starting material, at temperatures of from about 0xc2x0 C. to 25xc2x0 C., preferably less than 15xc2x0 C., to prepare IX.
Hydrolysis and decarboxylation of IX is achieved by refluxing with an aqueous acid, such as hydrochloric acid, for from about 1 to 24 hours. The solution containing the decarboxylated product VIII is neutralized to adjust the pH to about 7.0-7.5, then reacted with cyclohexanedione VII (preferably at equimolar concentrations) and a base, preferably sodium hydroxide, to yield the triketone monohydrate VI as a precipitate which may be purified and isolated, desired. The reaction is preferably conducted at temperatures of from xe2x88x9220xc2x0 C. to ambient temperatures and is substantially complete in about 1 to 24 hours.
The above reactions are preferably run as a xe2x80x9cone potxe2x80x9d process with the reactants added to the reaction vessel in the order given above. Preferably, the reaction is allowed to proceed without isolating compounds of formula IX or VIII, thus avoiding exposure to these volatile lachrymators.
Preparation of V is achieved by refluxing VI in a high boiling non-polar solvent which forms an azeotrope with water, preferably toluene, with an equimolar quantity of an amine of the formula R1NH2, where R1 is as defined above. When R1 is hydrogen, hexamethyldisilazane or ammonia may be used.
Solvents with a boiling point of at least 100xc2x0 C. are preferred, such as toluene, xylene, cymene, benzene, 1,2-dichloroethane or mesitylene, thus eliminating the need for a pressure reactor. Sufficient solvent should be employed to ensure that all compounds stay in solution until the reaction is substantially complete in about 1 to 24 hours.